tetano
Editor, Senior Moderator
Antiviral Res
. 2022 Jun 7;204:105350.
doi: 10.1016/j.antiviral.2022.105350. Online ahead of print.
Discovery of novel SARS-CoV-2 inhibitors targeting the main protease M [SUP]pro[/SUP] by virtual screenings and hit optimization
Beatrice Mercorelli[SUP] 1 [/SUP], Jenny Desantis[SUP] 2 [/SUP], Marta Celegato[SUP] 1 [/SUP], Alessandro Bazzacco[SUP] 1 [/SUP], Lydia Siragusa[SUP] 3 [/SUP], Paolo Benedetti[SUP] 4 [/SUP], Michela Eleuteri[SUP] 2 [/SUP], Federico Croci[SUP] 2 [/SUP], Gabriele Cruciani[SUP] 2 [/SUP], Laura Goracci[SUP] 5 [/SUP], Arianna Loregian[SUP] 6 [/SUP]
Affiliations
Abstract
Two years after its emergence, SARS-CoV-2 still represents a serious and global threat to human health. Antiviral drug development usually takes a long time and, to increase the chances of success, chemical variability of hit compounds represents a valuable source for the discovery of new antivirals. In this work, we applied a platform of variably oriented virtual screening campaigns to seek for novel chemical scaffolds for SARS-CoV-2 main protease (M[SUP]pro[/SUP]) inhibitors. The study on the resulting 30 best hits led to the identification of a series of structurally unrelated M[SUP]pro[/SUP] inhibitors. Some of them exhibited antiviral activity in the low micromolar range against SARS-CoV-2 and other human coronaviruses (HCoVs) in different cell lines. Time-of-addition experiments demonstrated an antiviral effect during the viral replication cycle at a time frame consistent with the inhibition of SARS-CoV-2 M[SUP]pro[/SUP] activity. As a proof-of-concept, to validate the pharmaceutical potential of the selected hits against SARS-CoV-2, we rationally optimized one of the hit compounds and obtained two potent SARS-CoV-2 inhibitors with increased activity against M[SUP]pro[/SUP] both in vitro and in a cellular context, as well as against SARS-CoV-2 replication in infected cells. This study significantly contributes to the expansion of the chemical variability of SARS-CoV-2 M[SUP]pro[/SUP] inhibitors and provides new scaffolds to be exploited for pan-coronavirus antiviral drug development.
Keywords: Antivirals; Main protease M(pro); SARS-CoV-2; Virtual screening.
. 2022 Jun 7;204:105350.
doi: 10.1016/j.antiviral.2022.105350. Online ahead of print.
Discovery of novel SARS-CoV-2 inhibitors targeting the main protease M [SUP]pro[/SUP] by virtual screenings and hit optimization
Beatrice Mercorelli[SUP] 1 [/SUP], Jenny Desantis[SUP] 2 [/SUP], Marta Celegato[SUP] 1 [/SUP], Alessandro Bazzacco[SUP] 1 [/SUP], Lydia Siragusa[SUP] 3 [/SUP], Paolo Benedetti[SUP] 4 [/SUP], Michela Eleuteri[SUP] 2 [/SUP], Federico Croci[SUP] 2 [/SUP], Gabriele Cruciani[SUP] 2 [/SUP], Laura Goracci[SUP] 5 [/SUP], Arianna Loregian[SUP] 6 [/SUP]
Affiliations
- PMID: 35688349
- PMCID: PMC9172283
- DOI: 10.1016/j.antiviral.2022.105350
Abstract
Two years after its emergence, SARS-CoV-2 still represents a serious and global threat to human health. Antiviral drug development usually takes a long time and, to increase the chances of success, chemical variability of hit compounds represents a valuable source for the discovery of new antivirals. In this work, we applied a platform of variably oriented virtual screening campaigns to seek for novel chemical scaffolds for SARS-CoV-2 main protease (M[SUP]pro[/SUP]) inhibitors. The study on the resulting 30 best hits led to the identification of a series of structurally unrelated M[SUP]pro[/SUP] inhibitors. Some of them exhibited antiviral activity in the low micromolar range against SARS-CoV-2 and other human coronaviruses (HCoVs) in different cell lines. Time-of-addition experiments demonstrated an antiviral effect during the viral replication cycle at a time frame consistent with the inhibition of SARS-CoV-2 M[SUP]pro[/SUP] activity. As a proof-of-concept, to validate the pharmaceutical potential of the selected hits against SARS-CoV-2, we rationally optimized one of the hit compounds and obtained two potent SARS-CoV-2 inhibitors with increased activity against M[SUP]pro[/SUP] both in vitro and in a cellular context, as well as against SARS-CoV-2 replication in infected cells. This study significantly contributes to the expansion of the chemical variability of SARS-CoV-2 M[SUP]pro[/SUP] inhibitors and provides new scaffolds to be exploited for pan-coronavirus antiviral drug development.
Keywords: Antivirals; Main protease M(pro); SARS-CoV-2; Virtual screening.